Cardiovascular outcomes in patients with chronic kidney disease and COVID-19: a multi-regional data-linkage study

Background Data describing cardiovascular outcomes in patients with COVID-19 and chronic kidney disease (CKD) are lacking. We compared cardiovascular outcomes of patients with and without COVID-19, stratified by CKD status. Methods This retrospective, multi-regional data-linkage study utilised individual patient-level data from two Scottish cohorts. All patients tested for SARS-CoV-2 in Cohort 1 between 01/02/2020 and 31/03/2021, and in Cohort 2 between 28/02/2020 and 08/02/2021, were included. Results Overall, 86 964 patients were tested for SARS-CoV-2. There were 36 904 patients (61±21 years, 58.1% women, 15.9% CKD, 10.1% COVID-19 positive) in Cohort 1 and 50 060 patients (63±20 years, 62.0% women, 16.4% CKD, 9.1% COVID-19 positive) in Cohort 2. In CKD patients, COVID-19 increased the risk of cardiovascular death by more than two-fold within 30 days (cause-specific hazard ratio [csHR] meta-estimate 2.34, 95% confidence interval [CI] 1.83–2.99), and by 57% at the end of follow-up (csHR meta-estimate 1.57, 95% CI 1.31–1.89). Similarly, the risk of all-cause death in COVID-19 positive versus negative CKD patients was greatest within 30 days (HR 4.53, 95% CI 3.97–5.16). Compared to patients without CKD, those with CKD had a higher risk of testing positive (11.5% versus 9.3%). Following a positive test, CKD patients had higher rates of cardiovascular death (11.1% versus 2.7%), cardiovascular complications, and cardiovascular hospitalisations (7.1% versus 3.3%) than those without CKD. Conclusions COVID-19 increases the risk of cardiovascular and all-cause death in CKD patients, especially in the short-term. CKD patients with COVID-19 are also at a disproportionate risk of cardiovascular complications than those without CKD.


Introduction
Coronavirus disease 2019 , the disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), 1 has had an unprecedented public health, societal and economic impact. Disease severity in patients with COVID-19 can vary markedly, from no symptoms or a mild respiratory illness, to life-threatening pulmonary and extra-pulmonary complications and death. 2 Several factors have been identified that increase disease severity. These include older age, male sex, social deprivation, obesity, and comorbidities such as cardiovascular disease and chronic kidney disease (CKD). [3][4][5][6][7][8] The risk of critical illness and death following COVID-19 increases as kidney function declines, such that patients with the most advanced CKD have the poorest outcomes. 4,[9][10][11] The commonest complication of CKD is cardiovascular disease. 12 As estimated glomerular filtration rate (eGFR) declines, the risk of cardiovascular disease and major adverse cardiovascular events increases. 13 Whilst pre-existing cardiovascular disease is a risk factor for COVID-19 severity, several studies have also suggested that myocardial injury and cardiovascular complications are common following COVID-19 and associated with worse outcomes for these patients. [14][15][16] However, data describing the nature and frequency of cardiovascular outcomes in patients with CKD and COVID-19 are lacking. Specifically, it is unclear how COVID-19 modifies the existing cardiovascular risk in patients with CKD in the short-and medium-term. In this unique multiregional data-linkage study, we evaluated the clinical characteristics and cardiovascular outcomes of patients with and without COVID-19, stratified by the presence or absence of CKD.

Baseline characteristics of patients with CKD according to COVID-19 status
In patients with CKD, those with COVID-19 were older and more socially deprived than those without COVID-19 ( Table 1). Although SARS-CoV-2 testing was performed more frequently in women than in men with CKD (Cohort 1: 53.8% versus 46.2%; Cohort 2: 59.5% versus 40.5%) (Supplementary Table 3), the proportion of women testing positive and negative was similar (Cohort 1: 52.3% versus 54.0%; Cohort 2: 58.0% versus 59.7%) ( Table 1). Patients with CKD who tested positive had higher rates of cardiovascular comorbidity but similar eGFR compared to patients who tested negative. Despite this, across both cohorts, patients with CKD who tested positive were less likely to be prescribed an ACE-inhibitor or ARB at the time of their index SARS-CoV-2 test than those who tested negative (

Outcomes of patients with CKD according to COVID-19 status
In patients with CKD, the crude rate of cardiovascular death at 30 days in those with  was double that of patients without COVID-19 (Cohort 1: 7.8% versus 3.4%; Cohort 2: 7.2% versus 3.5%) ( Table 2; Figure 1a; Supplementary Table 5). After balancing differences in covariates between positive and negative patients (Supplementary Figure 2)and following adjustment for confoundersthis increase in short-term cardiovascular risk persisted and was more than two-fold higher in positive than in negative patients at 30 days (cause-specific hazard ratio [csHR] metaestimate 2.34, 95% confidence interval [CI] 1.83 to 2.99) (Figure 2a). By the end of study followup, the difference in cardiovascular risk between positive and negative patients with CKD had narrowed (csHR meta-estimate 1.57, 95% CI 1.31 to 1.89) (Figures 1a & 2a).
In patients with CKD, the risk of all-cause death at 30 days in those with COVID-19 was substantially higher than in those without COVID- 19 Table 5). In the fully adjusted models, the risk of all-cause death in patients with CKD and COVID-19 was increased more than four-fold at 30 days (HR meta-estimate 4.53, 95% CI 3.97 to 5.16), and by more than two-fold overall (HR meta-estimate 2.41, 95% CI 2.17 to 2.64) compared to those with CKD testing negative. In contrast, cardiovascular complications and subsequent hospitalisations were lower in positive than in negative patients with CKD at 30 days, 90 days and to the end of study follow-up ( Table 2).
In a sensitivity analysis restricted to patients with CKD not hospitalised either in the week before or in the two weeks following their index COVID-19 test, overall rates of cardiovascular and all-cause death were lower than those reported in the primary analysis (Supplementary Table 6). However, COVID-19 was associated with a significantly increased risk of cardiovascular and all-cause death at all time points, especially in the short-terma pattern which was comparable to the primary analysis (Supplementary Table 7).

Outcomes of patients with COVID-19 according to CKD status and eGFR
In patients with COVID-19, those with CKD had a higher risk of cardiovascular death than those without CKD (csHR meta-estimate 1.64, 95% CI 1.29 to 2.10) (Supplementary Table 8 Figures 3 & 4). When eGFR was analysed as a continuous variable, the risk of both cardiovascular and all-cause death increased as kidney function declined (Supplementary Figure 5).
In patients with COVID-19, CKD was associated with an increased risk of COVID-19-related death (csHR meta-estimate 1.27, 95% CI 1.12 to 1.43) (Supplementary Table 8 Figure 6). Again, the risk of COVID-19-related death increased significantly as eGFR declined, even after adjustment for confounders (Supplementary Figure 7). Rates of cardiovascular complications and subsequent hospitalisations were also higher in COVID-19 positive patients with CKD than without (Supplementary Table 8).

& Supplementary
The outcomes of patients without CKD summarised according to COVID-19 status (

Discussion
In this multi-regional data-linkage study, we utilised a robust statistical approach combining multivariable outcome regression with propensity score weighting to evaluate the outcomes of ~87,000 patients with and without CKD tested for SARS-CoV-2. Overall, one-in-ten patients had a positive SARS-CoV-2 test. In patients with CKD, those with COVID-19 had a higher risk of cardiovascular and all-cause death than those without COVID-19 throughout follow-up, but especially within 30 days of SARS-CoV-2 testing. During this early period, patients with CKD and COVID-19 had a more than two-fold increased risk of cardiovascular deathand a more than fourfold increased risk of all-cause deaththan CKD patients testing negative. Compared to patients without CKD, those with CKD were also more likely to test positive. Following a positive test, CKD patients had higher rates of cardiovascular complications, including hospitalisations, and cardiovascular death than those without CKD. Moreover, the risks of cardiovascular, COVID-19related, and all-cause death increased as kidney function declined.
Our study has several strengths. First, its multi-regional design combined high-fidelity, high-quality Scottish linked healthcare data from patients undergoing community and hospital-based SARS-CoV-2 testing in three large NHS Health Boards (which together provide care for ~1.7 million people), irrespective of age, sex, socio-economic, kidney function, or hospitalisation status. Thus, the influence of case selection bias on our patient cohorts was minimised. Moreover, the accuracy and completion rates of the data sources used in this study were recently reported as 96% 26 and 99%, 27 respectively. Second, we utilised routinely-collected biochemistry data and criteria previously validated in electronic health records 19 to determine baseline kidney function, reducing the potential for misclassification of CKD status. Third, our inclusion of control populations -COVID-19 negative patients and patients without CKDalongside our use of a 'doubly-robust' estimator (concomitant multivariable outcome regression and weighting by the propensity score), limited the influence of confounding bias in our analyses. 23,28 Whilst the majority of patients with COVID-19 are considered to have increased cardiovascular risk, 29 few studies have examined the nature or extent of this risk in patients with CKD. 30 This is important given the well-recognised association between cardiovascular disease and CKD. 12,13 Here, in ~14,000 non-hospitalised and hospitalised patients with CKD tested for SARS-CoV-2, we found that COVID-19 more than doubled the risk of cardiovascular death within 30 days, and by 57% overall. Our secondary analysis showed that patients with COVID-19 and CKD had an increased risk of fatal and non-fatal myocardial infarction, heart failure and stroke compared to patients with COVID-19 but no CKD. In an adjusted model, CKD was also associated with a 64% increased risk of cardiovascular death in patients with COVID-19. In contrast, Rao and colleagues investigated the risk of cardiovascular complications in patients with COVID-19 but found no increase in risk in patients with CKD compared to those without CKD. 31 However, this study excluded non-hospitalised patients and patients who had tested negative for SARS-CoV-2, and relied on manual case note review to determine CKD status.
Our data add to the literature on COVID-19 outcomes in high-risk populations. However, a novel aspect of our approach is the inclusion of patients with CKD who tested negative for SARS-CoV-2.
Of the few studies that have included such patients, all have identified COVID-19 as being strongly associated with a poor prognosis. Indeed, a recent meta-analysis found that COVID-19 increased the odds of death approximately six-fold in patients with CKD. 32 This is more in-line with the risk of all-cause death we report in patients with CKD and COVID-19 at 30 days post-index test, consistent with the fact that most studies included in this meta-analysis reported in-hospital mortality only. Thus, our study is unique in reporting both short-and medium-term patient outcomes. Our study is also less biased towards severe COVID-19 as we included both nonhospitalised and hospitalised patients, making our results more accurate, representative, and informative for patients with all severities of CKD and COVID-19.
We found that, compared to patients without CKD, those with CKD were more likely to test positive for COVID-19. Thereafter, patients with COVID-19 and CKD had higher rates of fatal and non-fatal myocardial infarction, heart failure and stroke, cardiovascular hospitalisations, and cardiovascular, COVID-19-related, and all-cause death than patients with COVID-19 but no CKD. Few studies have reported on all these aspects. Our data are consistent with reports of an increasing incidence of COVID-19 as kidney function declines. 33,34 A number of factors likely contribute to this increased risk of COVID-19 in CKD, including case ascertainment bias (i.e. patients with CKD are more likely to be tested for SARS-CoV-2), greater viral exposure secondary to more frequent healthcare encounters (e.g. in-centre haemodialysis), 11 and an underlying increased predisposition to infection due to altered immune response. 35 We recognise some limitations. First, our inability to account for selected variables (e.g. body mass index, smoking status, type of atrial fibrillation [i.e. paroxysmal versus permanent; non-valvular or valvular]) means that we cannot exclude the potential for residual confounding. In addition, selected data relating to co-existing atrial fibrillation and prescribed cardiovascular medications were not available for patients included in Cohort 1. Second, rates of non-fatal cardiovascular complications, including atrial fibrillation and cardiovascular hospitalisations, may have been under-reported due to the competing risk of death in patients with COVID-19. Given the crude rates of non-fatal cardiovascular complications were generally higher in patients without  suggests that this might be the case. We overcame this when evaluating cardiovascular and COVID-19-related death by calculating cause-specific hazard ratios from our regression models.
Third, we excluded patients with no record of kidney function and those with only a single eGFR <60 ml/min/1.73 m 2 during the biochemistry 'lookback' period. Consequently, young or less comorbid patientswho are less likely to have had their kidney function testedmay be relatively under-represented. Finally, those patients with CKD who tested negative for SARS-CoV-2 were a relatively 'sick' control group; their all-cause mortality was substantially higher than might be expected for the CKD population in general. 36 One explanation for this is that SARS-CoV-2 PCR testing was largely restricted to the in-hospital setting for much of the early phase of the COVID-19 pandemic in the UK. 37 To address this issueand to illustrate the effect of including a more widely representative control groupwe performed a sensitivity analysis restricted to those patients not hospitalised either in the week before or in the two weeks following their index COVID-19 test, and demonstrated a similar pattern of increased risk of cardiovascular and all-cause death in patients with COVID-19 compared to those without.

Conclusions
Our unique and comprehensive analysis suggests that COVID-19 significantly increases the risk of cardiovascular complications and death in patients with CKD, especially in the short-term. There is an urgent need to prioritise COVID-19 vaccination and cardiovascular risk reduction strategies in all patients with CKD.         Figure 1).

Covariate-balanced propensity scoring and regression modelling
For our primary analysis, we sought to estimate the causal effect of COVID-19 on outcomes in patients with and without CKD, whilst for our secondary analysis, we sought to estimate the causal effect of CKD on outcomes in patients with and without COVID-19. With the aim of obtaining an unconfounded estimate, we utilised a 'doubly-robust' estimator with bootstrapped standard errors and 95% confidence intervals for the primary outcome analyses (Appendix). (12) This approach combines a multivariable outcome regression model with weighting by the covariate-balanced propensity score (CBPS). A key 7 strength of this method is that an unbiased effect estimate can still be obtained, even if one of the component models (either the outcome regression or CBPS model) has been mis-specified. (12,13) For the primary analysis, Cox regression was used to explore the association between COVID-19 status (the primary exposure) and cardiovascular and all-cause death (the primary outcomes). For the secondary analysis, Cox regression was used to explore the association between CKD status (the primary exposure) and cardiovascular, COVID-19 and all-cause death (the primary outcomes). For cardiovascular and COVID-19-related death, cause-specific hazard ratios were calculated to account for the competing risks of death from non-cardiovascular causes and death from non-COVID-19 causes, respectively.
For each analysis, we initially ran an unadjusted model before combining CBPS weighting and adjustment for several known confounders in a fully adjusted model. Using CBPS, covariates were balanced between exposure groups (COVID-19 and CKD status) in patients with and without CKD, and in patients with and without COVID-19 for the primary and secondary analyses, respectively. (14) Confounders were specified a priori and included age, sex, social demographic status, comorbidities (history of angina, myocardial infarction, heart failure, stroke, diabetes, cancer, chronic respiratory disease, chronic liver disease) and selected current medication (ACE-inhibitors/ARBs, immunosuppressant therapy) based on their potential relevance to COVID-19 outcomes. (15,16) For each primary outcome, hazard ratios derived from CBPS-weighted, fully-adjusted multivariable models in individual cohorts were pooled to obtain an overall meta-estimate. Both cohorts utilised similar patient populations based in the same country, whilst the design, definitions and overall methodology employed in each study cohort were also similar. Consequently, meta-estimates were computed using a fixed-effects model.
Thereafter, Cox regression models adjusting for the same confounders as before but with no CBPSweighting were used to estimate the association between eGFR (primary exposure) and the risk of 8 cardiovascular, all-cause, and COVID-19-related death in patients with and without COVID-19. For this analysis, eGFR was modelled as a continuous variable with restricted cubic splines using knots placed at the 5 th , 25 th , 50 th and 75 th centiles of eGFR measures in each cohort, as described previously. (17) Unadjusted and CBPS-weighted, multivariable Cox models were generated and fitted using the cobalt, rms, survival, and WeightIt packages, whilst meta-estimates were obtained using the meta package. All data were analysed using the R statistical programming language (Version 3.6.2, Vienna, Austria).

Missing data
Age, sex, comorbidity, prescribing, and outcome data were complete for all patients in both study cohorts. In Cohort 1, data relating to kidney function and social deprivation status were missing in 13.2% and 0.7% of all patient records, respectively. These were excluded from further analysis. In Cohort 2, data relating to social deprivation status were missing in 5.1%. For these records, hot deck imputation was implemented, with missing SIMD quintiles replaced by the observed value of another individual randomly chosen from all patients sharing a similar zip code.

Ethical (IRB) approval and statement of data transparency
The study was performed with the approvals of local Individual-level data are available via application to the DataLoch and Health Informatics Centre. Our analysis code is publicly available here.

Baseline characteristics of patients without CKD according to COVID-19 status
In patients without CKD, differences in baseline characteristics according to COVID-19 status were less marked across both cohorts ( Table 1). In patients who tested positive and negative, the proportion of women, rates of cardiovascular comorbidity and drug prescriptions, and eGFR were all similar.

Baseline characteristics of patients with COVID-19 according to CKD status
A positive SARS-CoV-2 test was more likely in patients with CKD than in those without CKD (Cohort 1: 12.5% versus 9.7%; Cohort 2: 10.5% versus 8.8%). In patients with COVID-19, those with CKD were older and had a greater burden of cardiovascular comorbidity than patients without CKD (Supplementary Table 4). The differences between patients with and without CKD were as marked in those without COVID-19.

Outcomes of patients without CKD according to COVID-19 status
In patients without CKD, the adjusted risk of cardiovascular death at 30 Figures 1b & 2b).

Outcomes of patients without COVID-19 according to CKD status and eGFR
Across both cohorts, significant differences in outcomes between those with and without CKD were also evident in patients without COVID-19. CKD was associated with an increased risk of cardiovascular  Figures 3 & 4). Finally, CKD was also 11 associated with higher rates of cardiovascular complications and subsequent hospitalisations in these patients.

12
Supplementary Text 1. List of International Classification of Diseases and BNF codes employed in study.

ICD-10
Any "C" code Exposure to immunosuppressants ATC L04 Abbreviations: ACE-inhibitor -angiotensin converting enzyme inhibitor; ARB -angiotensin receptor blocker; ATC -anatomical therapeutic classification, BNF -British National Formulary, ICD -international classification of diseases. *For chronic respiratory disease, the presence of a single ICD-10 code in SMR01 data OR a single BNF code in community prescription data was necessary and sufficient to assess the presence of the comorbidity. Values are mean ± SD, n (%), or median (interquartile range). Abbreviations: ACE-inhibitor -angiotensin converting enzyme inhibitor; ARB -angiotensin receptor blocker; CKD -chronic kidney disease; eGFRestimated glomerular filtration rate (ml/min/1.73 m 2 ); SIMD -Scottish index of multiple deprivation. *data not available for Cohort 1.